Analysis of viral genetic determinants involved in the pathogenesis of the acutely lethal SIVsmmPBj isolate has continued. Results of our mutational studies with the nef gene have confirmed that a tyrosine residue is critical for development of acute disease in SIVsmmPBj14-infected macaques. We have begun construction of sub-gene gag and tat chimeric viruses to examine the effects of these specific genes on pathogenesis. To investigate the role of activation in SIVsmmPBj pathogenesis, we have examined the effects of immunosuppressive therapy on PBj-induced acute disease. In vitro treatment with FK-506 was able to prevent PBj-induced PBMC proliferation, suggesting that this compound might prevent disease in vivo. Treatment of macaques with FK-506 was unable to prevent acute disease development when given as early as 1 day pre-infection. However, effects of FK-506 treatment were evident in tissue samples, which showed lower levels of virus and T-cell activation. Treatme nt of macaques with PMPA (a highly potent anti-retroviral drug) was able to prevent disease development, even if administered as late as five days post-infection. These results suggested to us that virus replication and not immune activation, was the essential element in acute disease development. FUNDING NIH / NCI $131,949 1/01/95 - 12/31/99 PUBLICATIONS Saucier, M.M., Hodge, S., Dewhurst, S., Gibson, T., Gibson, J.P., McClure, H.M. and Novembre, F.J. The tyrosine-17 residue of SIVsmmPBj14 Nef is necessary for acute pathogenesis and contributes to replication in macrophages. Virol 244:261-272, 1998. P51RR00165-38 1/1/1998 - 12/31/1998 Yerkes Regional Primate Research Center